What are the initial medical therapies for Cushing's disease?

Initial Medical Therapies for Cushing's Disease

Adrenal steroidogenesis inhibitors, specifically ketoconazole and metyrapone, are the most reliable first-line medical therapies for Cushing's disease when surgery is not immediately possible or has failed. 1

First-Line Medical Therapy Options

Ketoconazole

• Dosing: Initially 400-600 mg/day in 2-3 divided doses, increased to 800-1,200 mg/day until cortisol normalization, then maintenance dose of 400-800 mg/day 2, 1
• Efficacy: Normalizes urinary free cortisol (UFC) in approximately 64% of patients 2
• Onset: Response typically seen within days 1
• Monitoring:
  • Weekly liver function tests during first 6 months due to risk of hepatotoxicity 2
  • ACTH levels to monitor for tumor growth 1
• Side effects:
  • Hepatotoxicity (10-20% of patients) 2
  • Gastrointestinal disturbances (5-20%) 2
  • Skin rash (5%) 2
  • In men: hypogonadism and gynecomastia 2

Metyrapone

• Dosing: 15 mg/kg every 4 hours for 6 doses or 300 mg/m² every 4 hours (usual dose 250-750 mg every 4 hours) 2, 1
• Efficacy: Rapidly reduces cortisol levels within hours 1
• Best for: Severe hypercortisolism requiring rapid control 1
• Side effects:
  • Hirsutism, dizziness, arthralgia, fatigue, hypokalaemia, nausea 2
  • Hyperandrogenism and advanced bone age in children with prolonged use 2

Second-Line Options

Osilodrostat

• Efficacy: Achieves 86% UFC normalization with rapid cortisol reduction 1
• Advantage: Recently approved with high efficacy rates 1
• Currently being evaluated in pediatric patients in phase II trials 2

Pasireotide

• Mechanism: Targets somatostatin receptors in the pituitary 2
• Efficacy: 15-26% UFC normalization 1
• Best for: Patients with mild-to-moderate disease and visible tumor 1
• Administration: 0.6 mg or 0.9 mg subcutaneous injection twice daily 3
• Side effect: Significant hyperglycemia requiring monitoring 3

Cabergoline

• Mechanism: Dopamine agonist targeting pituitary tumor 2
• Efficacy: Effective in ~40% of patients 1
• Dosing: Up to 7 mg/week 1
• Best for: Mild disease, particularly in young women desiring pregnancy 1

Treatment Algorithm

1. For mild hypercortisolism:

   • Start with ketoconazole (400-600 mg/day) or metyrapone (250 mg every 4-6 hours) 1
   • Monitor cortisol levels and adjust dose accordingly

2. For moderate hypercortisolism with visible tumor:

   • Consider cabergoline or pasireotide 1
   • Alternatively, use ketoconazole or metyrapone

3. For severe hypercortisolism:

   • Use metyrapone for rapid cortisol normalization 1
   • Alternative: ketoconazole at higher doses (up to 1200 mg/day) 2

4. For inadequate response to monotherapy:

   • Consider combination therapy: ketoconazole + metyrapone or ketoconazole + cabergoline 1

Special Considerations

Pediatric Patients

• Medical therapies should primarily be used to reduce cortisol burden while awaiting definitive surgery or radiotherapy effects 2, 1
• Careful titration required under experienced clinical teams 2
• Long-term use has limited role due to effects on growth and puberty 2

Monitoring Recommendations

• Efficacy monitoring: 24-hour UFC, morning cortisol, and late-night salivary cortisol 1
• Weekly glycemic monitoring for first 2-3 months (especially with pasireotide) 3
• For adrenal-targeting agents: monitor ACTH levels and MRI for tumor growth 1
• Liver function tests with ketoconazole 2
• Electrolytes with metyrapone (risk of hypokalaemia) 2

Common Pitfalls

1. Undertreatment: Persistent hypercortisolism leads to continued morbidity 1
2. Overtreatment: Can cause adrenal insufficiency requiring glucocorticoid replacement 1
3. Misinterpreting drug failure: Insufficient dosing may be mistaken for treatment resistance 1
4. Hepatotoxicity with ketoconazole: Requires regular monitoring of liver function 2
5. Drug interactions: Particularly important with ketoconazole 2
6. Loss of efficacy over time: Up to 23% of initially responsive patients may escape control 2

Remember that while medical therapy is valuable, transsphenoidal surgery remains the definitive first-line treatment for Cushing's disease when possible, with medical therapy serving as adjunctive treatment before surgery or when surgery fails or is contraindicated 4, 5.